A DPP inhibitor suppresses periodontitis via antibacterial effect targeting Porphyromonas gingivalis

Porphyromonas gingivalis is the most common periodontal pathogen. P. gingivalis dipeptidyl peptidase 7 (PgDPP7) belongs to a new class of serine peptidases, family S46. S46 peptidases are absent in mammals. Therefore, these enzymes are promising targets for novel antibacterial agents. In this study, inhibitors were designed based on the cocrystal structures of valyl-tyrosine and phenylalanyl-tyrosine, which bind to the active centers of DPP7 derived from bacteria, and dipeptide derivatives that inhibit PgDPP7 were obtained. The active compound KGDI-109, the first peptidyl inhibitor of S46 peptidases, exerted an inhibitory effect against P. gingivalis growth at a minimum inhibitory concentration of 1.56 µM. In C57BL/6 N male mice with induced periodontitis, the oral administration of KGDI-109 significantly suppressed alveolar bone resorption and reduced the amount of P. gingivalis in the oral cavity, indicating that the DPP inhibitor suppresses periodontal disease by its antibacterial activity. This dipeptide derivative did not inhibit the growth of other oral bacteria, and its antibacterial action was presumed to target bacteria possessing DPP, particularly P. gingivalis. Furthermore, KGDI-109 may be more effective than azithromycin in maintaining the gut microbial diversity and reducing adverse health effects. KGDI-109 can be a novel treatment for periodontal diseases targeting P. gingivalis.